Optically active N-aryl-β-amino acid compounds are important intermediate compounds etc. for pharmaceuticals as shown in Organic Letters, 2001, 3, 2585 to 2586.
As a production method for optically active N-aryl-β-amino acid compounds, for instance, a process involving diastereoselective reduction of N-aryl-β-dehydroamino acid menthyl ester is described in J. Org. Chem., 2002, 67, 4667 to 4679. However, a stoichiometric amount of L-menthol is required for this method. Moreover, several additional processes such as derivatization into the N-aryl-β-dehydroamino acid menthyl ester and final hydrolysis to obtain the desired compounds are necessary. In addition to this disadvantage, the ee (enantiomeric excess) of the N-aryl-β-amino acid compound obtained by this method is less than 60% and only the (S) isomer is prepared from the natural menthol ester and therefore the (R) isomer cannot be synthesized economically.
A process using a Reformatzky-type asymmetric addition reaction with aldimines as starting materials (Chemical Letters, 2001, (3), 254˜255) and a process using an asymmetric Mannich reaction (Tetrahedron, 2001, 57, 875˜877) were reported as other methods. However, in the case of the Reformatzky method, a hydroxy group is essential in the ortho-position of the aniline of the aldimine, and therefore the manufacturing of N-aryl-β-amino acids having no hydroxy group in 2-position of the phenyl group is not possible. The Mannich method requires a stoichiometric amount of acetates with axial chirality. Since the preparation of acetates with axial chirality is not easy, this is unlikely to be an economically superior method. For these reasons, neither method is a satisfactory process for industrial production.
A copper catalyzed coupling reaction using β-amino acids and aryl halides was also described (Organic Letters, 2001, 3 (16), 2585 to 2586). However, there is an environmental problem for this process considering about the issue of copper waste treatment. Furthermore, β-amino acids are not so readily available in commercial quantities. There are several synthetic methods to produce β-amino acids using inexpensive β-keto carboxylic acid compounds as starting materials, which include a method by azidaion of β-hydroxycarboxylic acid esters using the Mitsunobu reaction (Synlett, 1998, 11, 1189 to 1190) and a process by the substitution reaction of sulfonylated β-hydroxycarboxylic acid esters with azide or benzylamine followed by reduction (Tetrahedron Letters, 1987, 28, 3103 to 3106). However, these processes require rather longer reaction sequences such as asymmetric reduction of β-keto carboxylic acid compounds, sulfonylation, reaction with azide or benzylamine, hydrogenation with metal catalysts and arylation process with copper. Consequently, a method using the copper catalysts described above cannot be regarded as an industrially suitable process.